While we know that CD4+CD25+Foxp3+ regulatory T cells (Tregs) are a powerful tool in the resolution of gut inflammation, and that their secretion of IL-10 is critical to inflammatory bowel disease (IBD) remission, there is a major gap in identifying mechanisms for increasing Tregs in the intestine. We have now identified a new candidate mechanism to achieve this goal: apoC-III inhibition of lipid uptake in Tregs. Our preliminary data shows that apoC-III protects from IBD, whereas loss of apoC-III is detrimental. We hypothesize that a critical function of apoC-III is to regulate lipid uptake and metabolism in intestinal Tregs, which results in increased tolerogenicity in the gut. We will test this hypothesis in 2 Specific Aims: Specific aim 1 will test the hypothesis that apoC-III inhibits fatty acid uptake into intestinal Tregs, forcing Tregs to utilize alternative pathways to fuel oxidative phosphorylation, and that this switch in metabolism stimulates Treg proliferation in the intestine. We will also identify receptor-mediated mechanisms by which apoC-III inhibits lipid uptake. Specific Aim 2 will test whether this mechanism of Treg stimulation can be used therapeutically in 2 models of murine colitis. We will use multiple approaches to raise plasma apoC-III levels, and we will also inhibit lipid uptake in Tregs to identify whether this is sufficient to protect RAG-1-/- mice from T cell transfer-mediated colitis (a model most similar to the effector T cell mediated human colitis). These studies will define a critically important homeostatic function for apoC-III and lipid uptake by Tregs in the gut, and will determine the mechanism of therapeutic colitis protection via apoC-III stimulation of intestinal Tregs. Given the interest in inhibiting apoC-III via antisense inhibitors, the outcome of these studies will have a significant translational impact on how these inhibitors are prescribed to patients with IBD. Additionally, these studies may identify novel therapeutic strategies to raising intestinally resident, tolerogenic Tregs which could then be used in the large proportion of IBD patients (~30%) who are resistant to existing therapeutic approaches.